Obesity is widely recognized as a serious health problem for the developed countries, and has reached epidemic status in the United States. More than 50% of the U.S. population is considered overweight, with >25% diagnosed as clinically obese and at considerable risk for heart disease, non-insulin dependent diabetes mellitus (NIDDM), hypertension, and certain cancers. This epidemic presents a significant burden on the health care system as projected obesity treatment costs of more than $70 billion annually are expected in the U.S. alone. Strategies for treating obesity include reducing food intake or enhancing the expenditure of energy.
It has been demonstrated that, when injected into the third ventricle of the brain or intraperitoneally, a cyclic heptapeptide analog of α-melanocyte stimulating hormone (αMSH) having melanocortin-4 receptor (MC4-R) agonist activity caused long lasting inhibition of food intake in mice. This effect was reversible when co-administered with a MC4-R antagonist. (Fan, et al., Nature (1997) 385: 165-168) Therefore, agonists of MC4-R activity would be useful in treating or preventing obesity.
There are five known melanocortin receptors based on sequence homology that ranges from 35-60% homology between family members (Cone, et al., Rec. Prog. Hormone Res. (1996) 51: 287-318), but these receptors differ in their functions. For example, the MC1-R is a G-protein coupled receptor that regulates pigmentation in response to the αMSH, which is a potent agonist of MC1-R. (Cone, et al., ibid.). Agonism of the MC1-R receptor results in stimulation of the melanocytes which causes eumelanin and increases the risk for cancer of the skin. Agonism of MC1-R can also have neurological effects. Stimulation of MC2-R activity can result in carcinoma of adrenal tissue. The effects of agonism of the MC3-R and MC5-R are not yet known. All of the melanocortin receptors respond to the peptide hormone class of melanocyte stimulating hormones (MSH). These peptides are derived from pro-opiomelanocortin (POMC), a prohormone of 131 amino acids that is processed into three classes of hormones; the melanocortins (α, β and γ), adrenocorticotropin hormone (ACTH), and various endorphins (e.g. lipotropin) (Cone, et al., ibid.). Because of their different functions, simultaneous agonism of the activities of multiple melanocortin receptors has the potential of causing unwanted side effects. Therefore it is desirable that an agonist of MC4-R be more selective for the MC4-R than for one or more of the other melanocortin receptors.
Haskell-Luevano, et al. (Peptides (1996) 17(6): 995-1002) disclose peptides that contain the tripeptide (D)Phe-Arg-Trp and exhibit melanotropic (skin darkening) activity in the frog (Rana pipiens) skin bioassay. Haskell-Luevano, et al. (ibid.) do not disclose any compound of formula I or II described below.
Bednarek, et al. (Peptides (1999) 20: 401-409) and Bednarek, et al. (Biochem. Biophys. Res. Comm. (1999) 261: 209-213) disclose analogs of the cyclic peptide MT-II. They do not disclose any compound of formula I or II described below.